Download Resurrection of vitamin D deficiency and rickets.

Vitamin D: Is It A Miracle Cure?
Robert Coleman, M.D, F.A.C.E.
Cotton-O'Neil Diabetes & Endocrinology
Topeka, KS
Physiology of Vitamin D
Sources
Sunlight
1.7-dehydrocholesterol via UVB (290-315 nm) and heat
converted to Vitamin D3. UVB can also inactivate D
Diet
1.Oily Fish
2.Dairy
Supplements
1.Available as D3 and D2
Liver Metabolism
25 Hydroxylated in Liver by CYP2R1
Activation/Deactivation
Activated in kidney by 1 alpha hydroxylase in response to
1.Elevated PTH
2.Low Calcium
3.Low Phosphate
Then deactivated via 24 hydroxylase, oxidized, side chain cleaved,
and excreted as calcitroic acid
Basic Functions of 1,25-dihydroxy-Vitamin D
Osteoblast - Activation of preosteoclast to osteoclast leading to bone
resorption.
Gut - Absorption of calcium via activation of VDR-RXR within
lamina. Activates CaBP to bind and transport calcium across the gut
surface.
Kidney - decreases calcium excretion in the urine
Other regulatory functions:
Increased 24-hydroxylase to deactivate the D
Negative feedback on parathyroid hormone production
Vitamin D Deficiency
Definitions:
Deficient - 25-(OH)D level < 10. Consequences - impaired bone
mineralization leading to rickets/ostoemalacia
Vitamin D Insufficiency
Insufficient - 25-(OH)D level <30. Consequences - calcium
malabsorption, secondary hyperparathyroidism among multiple
others...
Bone
Osteoporosis/Osteomalacia/Rickets
Osteoporosis via calcium malabsorption and secondary
hyperparathyroidism.
Recent meta-analyses find low 25-D associated with increased
fracture risk.
Muscle Function and Falls
Muscle pain and weakness.
Biopsy proven atrophy of fast twitch (type II) fibers. These fibers are
first recruited to avoid falling.
Randomized prospective trials show vitamin D reduces fall risk by
20%.
Cancer
Vitamin D has antiproliferative and prodifferentiating effects on many
types of cells.
Small prospective trials of vitamin D in postmenopausal women
found calcium+D recuced overall cancer risk by 60%.
People living in higher latitudes have increased risk of Hodgkin's
lymphoma, colon, pancreatic, prostate, ovarian, breast cancer
compared to lower latitudes.
25-D levels below 20ng/dl associated with 30-50% increased risk of
colon, prostate, and breast cancer.
Immune System
Vitamin D deficiency associated with increased respiratory infections.
Vitamin D enhances monocyte mycobacterial killing by facilitating
production of cathelicidin, an antimicrobial protein.
Helper type 1 & 2 cells are vitamin D targets, causing a shift toward
an anti-inflammatory profile.
Vitamin D deficiency accociated with increased risk of autoimmune
and infectious diseases.
Diabetes/Cardiovascular Disease
Vitamin D increases insulin production/secretion
Observational studies associate low vitamin D with type 1 and 2
diabetes mellitus
Observational studies show association between low D and
cardiovascular disease. Potential mechanism includes D effect on
endothelium, vascular smooth muscle, and cardiomyocytes - all have
D receptors.
Prospective studies lacking for both of these conditions
Psychiatric
Vitamin D deficiency associated with increased incidence of
schizophrenia and depression. May even be associated with in utero
and early life levels - early brain development.
Who should be tested?
Although above complications are concerning, the amount of
prospective data clearly showing benefit of population-based
screening is still lacking. Therefore, risk based approach is
recommended:
Those at high risk for vitamin D deficiency for whom a prompt
response to optimization of vitamin D status could be expected such
as those with ...
Osteoporosis, fall history, high risk of falls, malabsorption syndromes
(celiac disease, radiation entertitis, bariatric surgery, etc), liver
disease, use of medications known to alter vitamin D status, those
with malignancy.
How much to replace
Multiple variables:
Varied recommendations - USDA 400-600 int. units daily, National
Osteoprosis Foundation 800-1000 daily, and other experts 2000+
daily.
Age - Older require higher intake than younger (lower capability of
skin production).
Race - Needs of African Americans > Hispanic > Caucasian
Individual differences beyond these
Various approaches to replacement
Sun exposure - risks of skin cancer, however judicious sun exposure
may offer greater benefit than risk. Some experts suggest 15 minutes
of arms/legs/face unprotected exposure daily, but variables including
pigmentation, latitude, and time of day.
Supplementation:
600,000 int. units of D2 over 2 months achieved 25-D levels over 30
ng/ml in 64% of patients
50,000 int. units of D2 weekly over 3 years achieved 25-D levels over
30ng/ml in 23/24 patients
Various approaches to replacement (2)
Rule of thumb: 1000 int. units of D3 daily expected to increase 25-D
levels by 10ng/ml
Vitamin D2 30% as effective in maintaining 25-D than D3. May need
to triple doses if using D2.
Suggestions for replacement in various
situations
Children:
Breast Feeding w/o D supplementation up to 1 year:
Preventative: 400 IU daily, sensible sun, 1-2000 IU D3 daily safe.
Supplementation 400-1000 IU daily
Deficiency: 200K IU every 3 months, 600K IU repeated in 12 wks, 12000 IU with calcium daily.
Inadequate sun/supplementation/dark skin - 1yr to 18:
Preventative: same as above
Deficiency: 50K IU of D2 weekly x 8 weeks
Replacement suggestions - Adults
Inadequate sun/supplementation or age > 50:
Prevention: 800-1000 IU D3 daily, 50K IU every 2-4 weeks, sensible
sun. Up to 10K IU D3/day safe up for 5 months. Maintenance 50K IU
D2 every 2-4 weeks
Deficiency: 50K IU D2 weekly x 8 weeks, repeat until 25-D >30
ng/ml
Pregnant/lactating:
Prevention: 1000-2000 IU D2 daily, 50K IU D2 every 2 weeks, up to
4000 IU of D3 daily safe for 5 months. Maintenance same.
Deficiency: same
Replacement suggestions - Adults
Malabsorption syndromes
Prevention: adequate UVB, 50K IU D2 every 1-7 days, up to 10K IU
D3/day safe for 5 months. Maint: 50K IU D2 weekly.
Deficiency: UVB or 50K IU D2 every 1-2 days.
Drugs that activate steroid and xenobiotic receptor and transplant
drugs
Prevention: 50K IU D2 every 2-7 days. Maint: 50K IU D2 every 1-4
weeks
Deficiency: same
References
Resurrection of vitamin D deficiency and rickets. Michael F.
Holick. J Clin Invest. 2006; 116(8):2062.
Medical Progress:Vitamin D Deficiency. Michael F Holick.
NEJM 2007; 357:266-281.
Low Vitamin D Status: Definition, Prevalence, Consequences, and
Correction. Neil Binkley. Endocrinol Metab Clin N Am 39 (2010)
287-301.
Vitamin D: Metabolism. Sylvia Christakos. Endocrinol Metab Clin N
Am 39 (2010) 243-253.